While long-term reversible contraceptives, such as IUDs and implantable time-released birth-control medications, have become popular methods for pregnancy prevention in females, comparable methods for males do not exist. Additionally, short-term reversible male contraceptives, such as male condoms, withdrawal and periodic abstinence have relatively high failure rates (Trussell J. Contraceptive failure in the United States. Contraception 2004; 70: 89-96) making them less than ideal solutions for male contraception. Furthermore, even these basic contraceptives may not be readily available or widely accepted by the populations of some countries. For these and many other reasons, a pressing need for long-term reversible male contraception currently exists, which has not yet been met.
To date, the only commonly available long-term male contraceptive method is vasectomy: a surgical procedure wherein the vasa deferentia of subjects are severed and cauterized, effectively preventing the passage of any sperm from the testes. Although a vasectomy is a highly effective measure of contraception, should the subject decide to undergo vasectomy reversal, known as a vasovasostomy, the cost to the subject can be very high and the procedure is not always successful.
Several attempts have been made to create an alternative to the vasectomy. Specifically, devices that block the vas deferens have been made of urethane and silicone plugs as well as injectable medical grade silicone and polyurethane rubber. These methods have been tested but have proven unsuccessful due to leakage and/or scarring (Tulsiani & Abou-Haila, 2008). Valves implanted into the vas deferens were also unsuccessful (See Hollander Published U.S. Patent Application US 2014/0048076). Intra Vas Devices have been tested in humans, including a urethane mesh plug using a flexible synthetic anchored to the vas wall (Song et al., 2006). However, this device proved less effective than vasectomy in Phase 2 clinical trials and has been abandoned.
The use of a styrene maleic-based polymer to create a long-term reversible male contraceptive has been previously disclosed. Specifically, Guha (U.S. Pat. No. 5,488,075 and U.S. Patent App. 2011/0002979) has disclosed a polymer for use in vasa deferentia, created from a solution of styrene maleic anhydride or mixtures comprising less than equal parts of styrene maleic anhydride and styrene maleic acid, with the majority being the anhydride. While Guha has claimed to have disclosed a form of male contraception that is both effective and reversible, it has not yet gained regulatory approval despite a multi-decade development process. The disadvantages of this method have been shown to exist both in the synthesis of the styrene maleic-based polymer and its use. Firstly, the synthesis of Guha's polymer calls for the use of gamma irradiation to initiate free radical polymerization of the styrene maleic monomers. The use of gamma radiation can be hazardous and is not convenient or practical for either widespread small-scale synthesis or large-scale manufacturing. Furthermore, Guha's method requires onerous purification steps that call for retorting, organic/aqueous crystallization/separation and other difficult manufacturing processes.
It is of critical note, and point of difference with the present invention, that Guha teaches a composition that is comprised of styrene maleic anhydride for injection. Although he describes that once injected into the body the anhydride residues convert to an acid (and which he asserts provide a stable charge and pH effect that deactivates the sperm), his teachings include that a product must contain maleic anhydride on injection to perform acceptably. The present compositions and methods are based almost entirely on styrene maleic acid rather than styrene maleic anhydride. This use of styrene maleic acid over styrene maleic anhydride is based upon critical inventive discoveries. It has been discovered that an anhydride is not easily stabilized in dimethyl sulfoxide (DMSO) due to residual water in commercially available DMSO (and its highly hygroscopic nature). The inability to stabilize the anhydride makes manufacturing, quality control and shelf-life difficult to manage, and could result in product at time of injection with variable and unpredictable viscosity and other characteristics. It has been observed that polymers with elevated anhydride, or entirely anhydride, formed harder, semi-rigid solids on injection that may present risk of complications to the patient until the plug can later convert to the soft gelatinous acid form. In our research, and in direct contradiction to the teachings of Guha, it has been presently determined that an acid-based polymer can easily be produced, which can be stabilized in DMSO and can have well-controlled quality and consistency required for an injectable medical product, while providing durable contraceptive function and handling characteristics. Moreover, upon injection, in direct contradiction to the teachings of Guha, the present compositions can readily form a soft, stable space-filling plug that can provide durable and reversible blockage to the passage of sperm. In sum, the present compositions and methods show that it is unnecessary—in fact unfavorable—to produce a “prodrug” anhydride-based polymer that would convert in vivo to the active agent. Rather the present disclosure proves that the acid form can be produced and directly used as an effective occlusion agent.
Guha's method creates a styrene maleic anhydride bulk having a molecular weight between 60-100 kilodaltons (kDa) with Guha's preferred range being between 70-80 kDa. The resulting styrene maleic anhydride bulk can be mixed with a lesser amount of styrene maleic acid bulk to form a mixed polymer. This mixed polymer is then added to DMSO to create an injectable solution, which can be introduced into the vas deferens via needle and syringe.
Interestingly, Guha does not teach the creation of an impenetrable occlusion. Rather, Guha believes that his polymer chemically inactivates sperm as it passes though openings in the injected polymer, due to charges created by a residue in the polymer containing both styrene maleic anhydride and styrene maleic acid. Specifically, Guha teaches that his polymer leaves open passages having a charged surface across which sperm cells must traverse and thereby become inactivated. While Guha may or may not be correct that his disclosed polymer has the ability to deactivate all of the sperm that passes through it, the formation of an occlusion in the vas deferens that prevents passage of all sperm cells through the vas deferens would eliminate the need for such chemical deactivation.
The field of male contraception does not have, and currently needs, a long-term reversible male contraceptive comprising a hydrogel tissue bridge that can create an occlusion within the vas deferens. The polymer required to create such an occlusion must have flow properties which allow it to fill small spaces and should set up as a plug that is impenetrable to sperm, while preferably still allowing the passage of other bodily fluids. It would be preferable that this plug remain soft and flexible to avoid damage to surrounding tissues and be more comfortable for the patient than would a rigid plug.